Dyspareunia is the medical term for painful sexual intercourse. Dyspareunia is defined as persistent or recurrent genital pain that occurs just before, during or after intercourse. It is estimated that as many as 60% of women experience painful intercourse at some point in their lives. Heim L J, Evaluation and differential diagnosis of dyspareunia, Am Fam Physician, 2001 Apr. 15, 63(8), 1535-1544. Painful intercourse can occur for a variety of reasons—ranging from structural problems to psychological concerns. Elements of the history and physical examination help to identify the etiology and guide treatment, in most cases. Perivaginal infections, for example, may be treated with antibiotic or antifungal mediations based on microscopy or culture results. Endometriosis may be treated with nonsteroidal anti-inflammatory drugs, contraceptives or gonadotropin-releasing hormone agonists. Uterine myomas may be treated with surgery. Seehusen D A, et al., Dyspareunia in Women, Am Fam Physician, 2014 Oct. 1, 90(7), 465-470.
Genitourinary symptoms are common in postmenopausal women, including vaginal dryness and dyspareunia—which are “the most bothersome symptoms” in clinical trials. Ettinger B, et al., Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach. Menopause, 2008 Sep.-Oct., 15(5), 885-889. It is estimated that 84.2% of woman at 6 years post menopause will manifest genitourinary syndrome of menopause (“GSM”), with 100% of those reporting vaginal dryness and 77.6% reporting dyspareunia. Palma F, et al., Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: The AGATA study. Maturitas, 2016 January, 83, 40-44. Traditionally this had been felt to be related to decline in estrogen with atrophy of vulvar, vaginal and urinary tract epithelium, tissues which are rich in estrogen receptors; and a decline in lubrication as well as increase in vaginal pH, and was referred to as vulvovaginal atrophy or atrophic vaginitis. In 2014, the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) agreed that the term genitourinary syndrome of menopause (GSM) was a more accurate and acceptable term. GSM encompasses both symptoms including,: genital dryness, decreased lubrication with sexual activity, discomfort or pain with sexual activity, post-coital bleeding, decreased arousal, irritation/burning/itching of vulva or vagina, dysuria, and urinary frequency/urgency as well as the following signs including, decreased moisture, decreased elasticity, resorption of labia minora, pallor/erythema, loss of vaginal rugae, tissue fragility, urethral eversion or prolapse, introital retraction and recurrent urinary tract infections. Supportive findings include a pH greater than 5, increased parabasal cell on maturation index and decreased superficial cells. The presumptive etiology of this syndrome is related to a decline in estrogen, leading to atrophic changes in the vulvovaginal tissues, decrease in lubrication, and an increase in pH. Portman, D J, et al., Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and The North American Menopause Society, J Sex Med, 2014 Dec., 11(12), 2865-72. Treatments have focused on increasing the thickness of the tissues and/or lowering the vaginal pH. Treatments effective in achieving these objectives have included estrogens (topically or systemically) or the selective estrogen receptor modulator, ospemifene. Sturdee D W, et al., Recommendations for the management of postmenopausal vaginal atrophy, Climacteric 2010 Dec., 13(6), 509-522; Bachmann GA, et al., Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study, Menopause, 2010 May-Jun., 17(3), 480-486. Non-hormonal therapies include vaginal lubricants and moisturizers, which do not reverse atrophic changes but enhance comfort.
A review of several large studies examining the relationship between vaginal atrophy and dyspareunia, however, found no association between the occurrence or severity of atrophy of vaginal tissues and post-menopausal dyspareunia. Kao A, et al., Dyspareunia in postmenopausal women: A critical review. Pain Res Manag, 2008 May-Jun., 13(3), 243-254. Recent studies suggest that another mechanism, related to hyperproliferation of a neural network in the vulvar vestibule, —part of the external female genitalia anterior to the vagina, which is commonly seen in estrogen deficient states and may be an important mediator of dyspareunia in the genitourinary syndrome of menopause. Leclair, C M, et al. Histopathologic characteristics of menopausal vestibulodynia Obstet Gynecol, 2013 Oct., 122(4), 787-793; Goetsch, M F, et al., Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial Obstet Gynecol, 2014 Jun., 123(6), 1231-1236. The application of topical anesthetic (4% lidocaine aqueous solution) to the localized area of pain in the vulvar vestibule, in conjunction with silicone based lubricant, has been shown to effectively extinguish this pain, without side effects, and to enable comfortable intercourse in breast cancer survivors with dyspareunia. Goetsch M F, et al., A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial, J Clin Oncol, 2015 Oct. 20, 33(30), 3394-3400.
Prior art attempts at creating an effective aqueous gel for vaginal use include United States Patent Application No. 2016/0220601 (“the 601 application”) directed to a composition for vaginal application containing a sulfated polysaccharide, a natural quaternary polymer, a quaternary molecular compound, a metalloproteinase inhibitor anti-inflammatory agent and an acid pH buffering system. This specific combination is shown to be necessary to provide optimal lubrication and hydration as the composition is directed to reducing irritation and strengthening vaginal tissue among others conditions.
Prior art attempts at creating a local anesthetic gel include WIPO Publication No. 2015/177288 (“the '288 application”) directed to an aqueous gel formulation suitable for oral use containing an anesthetic, a polyethylene oxide, a polysaccharide and a preservative. However, the '288 publication requires a polyethylene oxide to obtain its desired properties such as being stringent without being tacky. U.S. Pat. No. 8,759,401 (“the '401 patent”), assigned to Akorn, Inc., is directed to an aqueous gel formulation suitable for administration to the eye containing lidocaine hydrochloride, a viscoelastic polymer and sodium chloride. However, the '401 patent requires a pH of at least 5.0 and no preservatives because of the need to be comfortably applied to the eye.
Thus, there remains a need in the art for aqueous gel formulations that are specifically formulated to topically treat vulvovaginal pain.